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Purpose: The ETOP 10-16 BOOSTER study was a randomized phase II trial of osimertinib and bevacizumab therapy versus osimertinib therapy in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously., Experimental Design: Next-generation sequencing (Guardant360) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored, and molecular alterations at progression were described., Results: A total of 136 patients (88% of 155 randomized) had plasma samples at baseline (68 per arm), 110 (71%) at week 9, and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found to differ by smoking status (interaction P = 0.046), with the effect of smoking also differing by baseline EGFR T790M (interaction P = 0.033), whereas both TP53 at baseline and the tissue EGFR exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (P = 0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (P = 0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arms, respectively., Conclusions: The differential effect of treatment by smoking was not explained by TP53 mutations or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected, but no novel molecular alterations were identified in the combination arm., (©2024 American Association for Cancer Research.)

Background: Perioperative immunotherapy improves short-term outcomes in resectable non-small-cell lung cancer (NSCLC). We now report 5-year survival from the NADIM trial to assess its long-term benefit., Methods: NADIM was a multicentre, single-arm, phase 2 trial conducted across 18 hospitals in Spain. Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had histologically or cytologically confirmed, treatment-naive, resectable stage IIIA NSCLC (American Joint Committee on Cancer, 7th edition criteria). The neoadjuvant treatment consisted of three cycles of intravenous paclitaxel (200 mg/m 2 ) and carboplatin (area under the curve 6 mg/mL per min) with nivolumab (360 mg). After surgery, 1 year of adjuvant treatment with intravenous nivolumab monotherapy was administered (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was 24-month progression-free survival, with 5-year progression-free survival and overall survival as secondary endpoints, assessed in the intention-to-treat population (ie, all patients who received neoadjuvant treatment). Toxicity profile was also assessed as a secondary endpoint. This trial is registered at ClinicalTrials.gov (NCT03081689) and is complete; this is the final report of the trial., Findings: Between April 26, 2017, and Aug 25, 2018, 51 patients were assessed for eligibility, of whom 46 comprised the intention-to-treat population (34 [74%] male and 12 [26%] female, median age 63 years [IQR 58-70]). Follow-up was concluded at 60 months (data cutoff July 11, 2023; median follow-up 60·0 months [IQR 60·0-60·0]). 5-year progression-free survival in the intention-to-treat population was 65·0% (95% CI 49·4-76·9), and overall survival was 69·3% (53·7-80·6). Disease progression occurred in 11 (24%) patients; 14 (30%) patients died, including nine (20%) from disease relapse and five (11%) from non-tumour-related causes. Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 14 (30%) of 46 patients during neoadjuvant treatment and in seven (19%) of 37 during adjuvant treatment. The most common grade 3 or worse TRAEs were increased lipase and febrile neutropenia (three [7%] each) during neoadjuvant treatment, and elevated serum lipase (four [7%]) and elevated serum amylase (three [8%]) during adjuvant treatment. Serious TRAEs included elevated serum lipase and neutropenia (one [2%] each) during neoadjuvant treatment, and elevated serum lipase (one [3%]) during adjuvant treatment. No treatment-related surgery delays, deaths, or unexpected long-term toxicities were reported., Interpretation: Perioperative chemoimmunotherapy showed a promising long-term benefit with no concerning safety data, reinforcing its use in resectable stage IIIA NSCLC., Funding: Bristol-Myers Squibb, Spanish Ministry of Science, Instituto de Salud Carlos III, European Union., Competing Interests: Declaration of interests MP reports non-financial support (reagents for T-cell receptor sequencing) from ThermoFisher Scientific; grants, consulting fees, and non-financial support from Bristol Myers Squibb, Roche, and AstraZeneca; and consulting fees from MSD and Takeda; outside the submitted work. EN reports grants from Roche, Pfizer, Bristol Myers Squibb, Merck, and Nanostring; consulting fees from Roche, Bristol Myers Squibb, Merck Sharpe & Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre, Qiagen, and Bayer; payment of honoraria from Roche, Bristol Myers Squibb, Merck Sharpe & Dohme, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, and Qiagen; support for attending meetings or travel from Takeda, MSD, Janssen, and Roche; and participation on advisory boards for Apollomics, Roche, and Pfizer. AI reports consulting fees from Pfizer, Amgen, and Astra Zeneca; payment for expert testimony from Bristol Myers Squibb, Roche, Pfizer, Astra Zeneca, and Takeda; support for attending meetings or travel from Roche, Takeda, and Pfizer; and participation on advisory boards for Roche and Bristol Myers Squibb. RG-C reports consulting fees from Bristol Myers Squibb, MSD, Roche, Pfizer, and AstraZeneca. MD reports consulting fees from AstraZeneca, Bristol Myers Squibb, MSD Oncology, Pfizer, Roche, and Takeda; and support for attending meetings or travel from AstraZeneca, MSD Oncology, Pfizer, and Takeda. BM reports consulting fees from Astra Zeneca and Amgen; payment or honoraria from Roche, Bristol Myers Squibb, and MSD; and support for attending meetings or travel from MSD and AstraZeneca. MM reports grants from Roche and Astra Zeneca; payment of honoraria from Roche, AstraZeneca, MSD, Pfizer, Helsinn, Cassen, Amgen, Janssen, Sanofi, Pierre Fabre, Bristol Myers Squibb, and Takeda; and support for attending meetings or travel from MSD, Roche, and AstraZeneca. DR-A reports honoraria for lectures from MSD, Roche, Bristol Myers Squibb, Novartis, Takeda, Lilly, and AstaZeneca; support for attending meetings or travel from Roche, MSD, Novartis, and Sanofi; and participation on advisory boards for Merck Sharpe & Dohme, Regeneron, Bristol Myers Squibb, GSK, and Lilly. AM-M reports consulting fees from AstraZeneca/MedImmune, Bristol Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, and Janssen; payment for expert testimony from AstraZeneca, MedImmune, Bristol Myers Squibb, and F. Hoffmann La Roche; support for attending meetings or travel from AstraZeneca, MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, Janssen, and Lilly; and participation on advisory boards for AstraZeneca, MedImmune, Merck Sharpe & Dohme, F. Hoffmann La Roche, and Bristol-Myers Squibb. JdC reports consulting fees from AstraZeneca, Bristol Myers Squibb, Roche, MSD, Boehringer, Janssen, Lilly, Sanofi, Takeda, Pfizer, and GSK; support for attending meeting or travel from AstraZeneca, MSD, and Roche; participation on advisory boards for AstraZeneca, Bristol Myers Squibb, Roche, MSD, Glaxo, Janssen, and Gilea; and speaker's bureau fees from AstraZeneca/MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, and Janssen. DG reports payment or honoraria from Astra Zeneca and Bristol Myers Squibb. VC reports consulting fees from Roche, AstraZeneca, MSD, Bristol Myers Squibb, Takeda, Sanofi, and Amgen; payment or honoraria from Roche, AstraZeneca, MSD, Bristol Myers Squibb, Takeda, SanofiI, and Amgen; and support for attending meetings or travel from AstraZeneca, Roche, MSD, and Takeda. RP reports payment or honoraria from Guardant Health and Pfizer; and support for attending meetings or travel from Merck Sharpe & Dohme; participation on an advisory board for AstraZeneca. AR reports payment or honoraria from Illumina, Health in Code, and ThermoFisher Scientific; support for attending meetings or travel from ThermoFisher Scientific, Bristol Myers Squibb Foundation, and Takeda; and advisory board participation for Takeda. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients., Methods: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety., Results: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%)., Conclusions: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: Immunotherapy-based approaches are standard first-line treatments for advanced/metastatic lung cancer or for chemoradiotherapy consolidation in locally advanced disease. Uncertainty on how to treat patients at disease progression prompted us to develop a consensus document on post-immunotherapy options in Spain for patients with advanced wild-type lung adenocarcinoma., Methods: After extensive literature review, a 5-member scientific committee generated 33 statements in 4 domains: general aspects (n = 4); post-durvalumab in locally advanced disease (n = 6); post-first-line immunotherapy ± chemotherapy in advanced/metastatic disease (n = 11); and post-first-line platinum-based chemotherapy in advanced/metastatic disease (n = 12). A panel of 26 lung cancer experts completed 2 Delphi iterations through an online platform rating their degree of agreement/disagreement (first-round scale 1-5 and second-round scale 1-4, 1 = strongly disagree, 4/5 = strongly agree) for each statement. Second-round consensus: ≥ 70% of responses were in categories 1/2 (disagreement) or 3/4 (agreement)., Results: Consensus was reached for 2/33 statements in the first Delphi round and in 29/31 statements in the second round. Important variables informing treatment at disease progression with an immunotherapy-based treatment include: disease aggressiveness, previous treatment, accumulated toxicity, progression-free interval, PD-L1 expression, and tumour mutational burden. A platinum-based chemotherapy should follow a first-line immunotherapy treatment without chemotherapy. Treatment with docetaxel + nintedanib may be appropriate post-durvalumab in refractory patients or following progression to first-line chemotherapy + immunotherapy, or second-line chemotherapy after first-line immunotherapy, or first-line chemotherapy in some patients with low/negative PD-L1 expression, or second-line immunotherapy after first-line chemotherapy., Conclusions: To support decision making following progression to immunotherapy-based treatment in patients with advanced wild-type lung adenocarcinoma, a consensus document has been developed.

Background: The goals of this multinational retrospective study were to describe treatment patterns and survival outcomes by receipt of molecular testing and molecular status of patients with advanced non-small cell lung cancer (NSCLC)., Methods: This chart review study, conducted in Italy, Spain, Germany, Australia, Japan, Korea, Taiwan, and Brazil, included 1440 patients with newly diagnosed advanced (stage IIIB/IV) NSCLC initiating systemic therapy from January 2011 through June 2013, with follow-up until July 2016. We evaluated treatment patterns and survival by histology, line of therapy, molecular testing, and test results for epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma kinase (ALK) rearrangement. Country-specific data were analyzed descriptively and presented as ranges (lowest to highest country). Overall survival (OS) was estimated using Kaplan-Meier method., Results: Patients with ≥1 molecular test varied from 43% (Brazil) to 85% (Taiwan). Numerically greater proportions of patients who were female, Asian, or never/former-smokers, and those with nonsquamous histology or stage-IV NSCLC, received a test. Testing was common for nonsquamous NSCLC (54%, Brazil, to 91%, Taiwan), with positive EGFR and ALK tests from 17% (Brazil and Spain) to 67% (Taiwan) and from 0% (Brazil) to 60% (Taiwan), respectively. First-line treatment regimens for nonsquamous NSCLC with positive EGFR/ALK tests included targeted therapy for 30% (Germany) to 89% (Japan); with negative/inconclusive test results, platinum-based combinations for 88% (Japan) to 98% (Brazil); and if not tested, platinum-based combinations for 80% (Australia) to 95% (Japan), except in Taiwan, where 44% received single agents. Median OS from first-line therapy initiation was 10.0 (Japan) to 26.7 (Taiwan) months for those tested and 7.6 (Australia/Brazil) to 19.3 (Taiwan) months for those not tested., Conclusions: We observed substantial variation among countries in testing percentages, treatment patterns, and survival outcomes. Efforts to optimize molecular testing rates should be implemented in the context of each country's health care scenario., Competing Interests: Dae Ho Lee reports honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, Jansen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, and Samyang Biopharm for participating in advisory boards; and receipt of consulting fees from the Ministry of Food and Drug Safety (MFDS), Korea, and Health Insurance Review and Assessment Service (HIRA), Korea. Ming-Sound Tsao reports honoraria for advisory board meetings from AstraZeneca, Bristol-Myers Squibb, Pfizer, Ventana/Roche, and Merck. Hiroshi Isobe has received payment for speaking engagements from AstraZeneca, Bristol-Myers Squibb, Kyowa Hakko Kirin, Chugai, Boehringer Ingelheim, Ono Pharmaceutical Co. Ltd., and Eli Lilly Japan, K.K. Smita Kothari, Ashwini Arunachalam, Xiting Cao, and Thomas Burke are employees of Merck & Co., Inc., Kenilworth, NJ, USA, which supplied the funding for this study. Amparo Valladares is an employee of Merck Sharp & Dohme de España S.A., Madrid, Spain. All other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib., Patients and Methods: ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS)., Results: Altogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9-12.2] with alectinib and 1.4 months (95% CI: 1.3-1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08-0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17-0.59); median PFS was 7.1 months (95% CI: 6.3-10.8) with alectinib and 1.6 months (95% CI: 1.3-4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks)., Conclusion: Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile., Trial Registration: ClinicalTrials.gov NCT02604342; Roche study MO29750.

The aim of this multinational retrospective cohort study, conducted at academic and community oncology centres, was to describe real-world treatment patterns for patients with a confirmed diagnosis of advanced/metastatic (stage IIIB/IV) non-small cell lung cancer (NSCLC) who initiated first-line systemic therapy from January 2011 through June 2014. The study included 1265 patients in Italy, Spain, Germany, Australia, Korea, Taiwan and Brazil. The proportion of patients with squamous versus non-squamous NSCLC was approximately 20% versus 75%, and associated patient demographic characteristics were similar in all countries, excepting race. Patients with squamous NSCLC were predominantly male and current/ex-smokers. Biomarker tests were performed for the majority of patients with non-squamous NSCLC, ranging from 54% (Brazil) to 91% in Taiwan, where, of those tested, 68% with non-squamous NSCLC had positive epidermal growth factor receptor (EGFR)-mutation status; in other countries the EGFR-positive percentages ranged from 17% (Spain/Brazil) to 40% (Korea). Platinum-based regimens were the most common first-line therapy in all countries except Taiwan, where gefitinib was the most common first-line agent. Median overall survival ranged from 9.3 months (Brazil) to 25.5 months (Taiwan). The diagnostic and treatment patterns recorded in this study were heterogeneous but largely in line with NSCLC guidelines during the study period., (© 2017 The Authors. European Journal of Cancer Care Published by John Wiley & Sons Ltd.)

Objectives: Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors., Patients and Methods: We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR12w). Pre-treatment plasma samples were required to assess T790M resistant mutation., Results: A total of 33 patients were enrolled in the phase I-II trial. The maximum tolerated dose was erlotinib 150 mg p.o., QD, and 400mg p.o., QD, on days 1-7 and 15-21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR12w was 28% (IC 95%: 18.0-37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43-8.45) and overall survival (OS) 10.3 months (95% CI: 2.4-18.1)., Conclusion: Full dose of continuous erlotinib with vorinostat 400mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Cisplatin plus oral vinorelbine, one of the standard treatments for metastatic non-small-cell lung cancer (NSCLC), is associated with a high rate of neutropenia, and a hemogram is performed on day 8. We analyzed the oncologists' opinions and the result of the hemogram on day 8 to address the question of whether this hemogram could be avoided., Materials and Methods: Fifty-eight chemotherapy-naive, advanced NSCLC patients were included. Each received intravenous doses of 75 mg/m(2) cisplatin on day 1 plus oral vinorelbine [60 mg/m(2) in the first cycle (80 mg/m(2) in subsequent cycles) on days 1 and 8], every 3 weeks, for a maximum of six cycles., Results: Out of 257 cycles analyzed, oral vinorelbine was administered on day 8 in 214 (83.2 %) and the dose was canceled in 6 cycles (2.3 %) due to hematological toxicity. On analyzing the patients to whom chemotherapy had been administered on day 8, based on medical opinion without the doctor knowing the hemogram result, we found that the cycle had been administered with a hemogram showing fewer than 1,500 × 10(6) neutrophils in only 3 of the 185 evaluable cycles [event rate of 1.6 %, with confidence interval 95 % = (0.34-4.67 %)]., Conclusion: The hemogram on day 8 can be avoided and oral vinorelbine administered in relative safety in patients with good performance status, when confirmed by the clinician's perception, thereby making this regimen more comfortable for the patient. This is the first prospective study to examine this issue.

Systemic chemotherapy (CT) with platinum-based doublets result in modest improvements in both overall survival (OS) and quality of life in good performance status patients with advanced non-small cell lung cancer (NSCLC). However, although substantial progress has been made in the therapeutic options currently available for these patients, the overall outcome remains poor. Maintenance therapy for patients who achieved at least stable disease after first-line treatment has been an area of intense investigation in recent years as a way of improving outcomes in metastatic NSCLC. Several alternative strategies for prolongation of initial treatment have been evaluated. These include the prolongation of the initial combination CT regimen until disease progression, unacceptable toxicity or a predefined greater number of cycles, continuation with a lower intensity version of the first-line CT regimen or administration of a new active agent immediately after completion of the first-line therapy (switch-maintenance or early second-line therapy). Treatments that have been studied in randomized trials to date include CT, molecularly targeted agents, and immunotherapy approaches. Phase III trials have not revealed a survival benefit for extended first-line CT with combination regimens for more than 4-6 cycles. Nevertheless, early second-line therapy with pemetrexed in nonsquamous tumours and erlotinib have demonstrated to improve OS results, especially in select patient groups characterized by histology and/or molecular profile. This article reviews recent data with maintenance therapy in advanced NSCLC and discusses the implications for routine patient care and future drug development., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC., Methods: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225., Findings: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes., Interpretation: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors., Funding: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We present the treatment rationale and study design of the AvaALL (MO22097; ClinicalTrials: NCT01351415) trial, a multicenter, open-label, randomized, two-arm, phase IIIb study. Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) whose disease has progressed after four to six cycles of first-line treatment with bevacizumab plus a platinum-based doublet and a minimum of two cycles of bevacizumab (monotherapy) maintenance treatment will be randomized in a 1:1 ratio to one of two study arms. Patients treated on arm A will receive bevacizumab 7.5 or 15 mg/kg intravenously (I.V.) on day 1, every 21 days plus, investigator's choice of agents indicated for use in second-line (limited to pemetrexed, docetaxel, or erlotinib) and subsequent lines of treatment. Patients treated on arm B, will receive investigator's choice of agents alone indicated for use in second-line and subsequent lines of treatment, but no further bevacizumab treatment. The primary endpoint of this study is overall survival (OS). Secondary endpoints include the 6-month, 12-month, and 18-month OS rates, progression-free survival, and time to progression at second and third progressive disease (PD), response rate, disease control rates, and duration of response at second and third PD. Additionally, efficacy in the subgroup of patients with adenocarcinoma, and the safety of bevacizumab treatment across multiple lines of treatment will be assessed. Exploratory objectives include assessment of the quality of life through multiple lines of treatment, comparison of the efficacy between Asian and non-Asian patients, and correlation of biomarkers with efficacy outcomes, disease response, and adverse events., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The purpose of this phase II trial was to determine the efficacy and safety of the XELOX (capecitabine/oxaliplatin) regimen as first-line therapy in the elderly patients with metastatic colorectal cancer (MCRC). A total of 50 patients with MCRC aged > or = 70 years received oxaliplatin 130 mg m(-2) on day 1 followed by oral capecitabine 1000 mg m(-2) twice daily on days 1-14 every 3 weeks. Patients with creatinine clearance 30-50 ml min(-1) received a reduced dose of capecitabine (750 mg m(-2) twice daily). By intent-to-treat analysis, the overall response rate was 36% (95% CI, 28-49%), with three (6%) complete and 15 (30%) partial responses. In total, 18 patients (36%) had stable disease and 14 (28%) progressed. The median times to disease progression and overall survival were 5.8 months (95% CI, 3.9-7.8 months) and 13.2 months (95% CI, 7.6-16.9 months), respectively. Capecitabine was well tolerated: grade 3/4 adverse events were observed in 14 (28%) patients: 11 (22%) diarrhoea, eight (16%) asthenia, seven (14%) nausea/vomiting, three (6%) neutropenia, three (6%) thrombocytopenia, and two (4%) hand-foot syndrome. There was one treatment-related death from diarrhoea and sepsis. In conclusion, XELOX is well tolerated in elderly patients, with respectable efficacy and a meaningful clinical benefit response. Given its ease of administration compared with combinations of oxaliplatin with 5-FU/LV, it represents a good therapeutic option in the elderly.

Purpose: To evaluate the efficacy and toxicity profile of the combination of docetaxel and prolonged gemcitabine infusion in front-line chemonaive patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: A total of 50 chemonaive patients diagnosed with advanced NSCLC according to the AJCC/TNM classification system were included in the present study. Treatment consisted of 1000 mg/m(2) gemcitabine given as a 100-min continuous infusion (10 mg/m(2) per min) on days 1 and 8 of each course and 75 mg/m(2) docetaxel as a 60-min infusion on day 8, repeating each course every 21 days., Results: The ECOG performance status of the patients were as follows: 0 (10%), 1 (60%), and 2 (30%). All patients had two-dimensionally measurable disease. Their median age was 63 years (range 41-75 years). Of the 50 patients, 28 (56%) had squamous cell carcinoma, 14 adenocarcinoma (28%), and 8 (16%) large-cell carcinoma, and 40% and 60% of patients presented with stage IIIB and IV disease, respectively. Of those with stage IV disease, 33% had more than one metastatic site. A total of 220 courses were administered with a median of five courses per patient. Of 46 patients assessed for response, 12 (26%) had a partial remission (95% CI 13-39%). In 19 patients (41%) the disease remained stable, while disease progression was observed in 15 (33%). The median time to disease progression was 4 months, and median survival time was 7 months. At 1 year, 25% of patients remained alive, and the main grade 3/4 toxicity (according to the WHO scale) consisted of neutropenia ( n=6, 12%), asthenia ( n=4, 8%), peripheral edema ( n=3, 6%), dyspnea ( n=3, 6%), and diarrhea ( n=2, 4%)., Conclusions: Prolonged gemcitabine infusion combined with docetaxel is well tolerated and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment. However, the prolonged infusion of gemcitabine did not appear to result in any improvement in outcome or toxicity versus the standard dose rate.

Background: The object of this phase II study was to assess the impact of preoperative external radiation therapy combined with UFT and leucovorin on tumor response, sphincter preservation and tumor control in patients with rectal carcinoma., Patients and Methods: Forty-one patients with resectable extraperitoneal rectal adenocarcinoma received radiation therapy and two courses of chemotherapy. Chemotherapy consisted of a 2-h infusion of 6S-steroisomer of leucovorin (6SLV) 250 mg/m2 on day 1, oral 6SLV 7.5 mg every 12 h on days 2-14, and UFT either 350 or 300 mg/m2 on days 1 to 14 every 28 days. Six additional courses of chemotherapy were given after surgery., Results: Seven of 16 patients (43%) who received 350 mg/m2/day of UFT had grade 3-4 diarrhea and two other patients (12%) had grade 3-4 dermatitis. The next 25 patients received 300 mg/m2/day of UFT and only 14% of them had grade 3-4 diarrhea. Surgery consisted of low-anterior resection in 26 patients (63%) and abdominal-perineal amputation in 15 (37%). There were six histological complete responses (15%). Downstaging occurred in 25 patients (63%). The overall survival at 3 years was 90% and the pelvic disease-free survival 92%., Conclusions: Preoperative therapy with radiotherapy and UFT-6SLV downstaged 63% of tumors and allowed a sphincter-preserving procedure in some patients. Toxicity was moderate. This scheme is convenient because of the oral administration of chemotherapy.

Objectives: New effective therapies are needed to improve the outcome of patients with advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess the response rate and survival obtained with a sequential regimen of chemotherapy., Patients and Methods: Patients with newly diagnosed stage IIIb-IV NSCLC were included. They all had measurable disease and a good performance status (0-2 in the Eastern Cooperative Oncology Group scale). Chemotherapy consisted of weekly paclitaxel 150 mg/m2 x 6, followed two weeks later by cisplatin 100 mg/m2 on day 1, gemcitabine 1,000 mg/m2 on days 1 and 14, and vinorelbine 25 mg/m2 on days 1 and 14 (CGV). CGV was administered every 28 days for a maximum of six courses., Results: Fifty-two patients were included, 19 (37%) with stage IIIb and 33 (63%) with stage IV disease. After therapy with weekly paclitaxel. 29 partial responses were obtained (56%, 95% confidence interval (95% CI): 38%-67%), whereas 15 patients had stable disease (29%) and eight had a progression (15%). After CGV, there were four complete remissions (8%) and 24 partial responses (46%), for an overall response rate of 54% (95% CI: 37%-65%). Eight patients had stable disease (15%) and 16 had a progression (31%). No patient progressing after paclitaxel responded to CGV, whereas 5 out of 15 patients with stable disease reached a partial response with CGV (33%). On the contrary, 5 out of 29 patients with a partial response to paclitaxel progressed after CGV (17%). Median survival has not been reached after a median follow-up of 14 months. Median time to progression was nine months. Fifty-six percent of patients remain alive at one year. Two hundred eighty-nine courses of paclitaxel and 170 of CGV were given, with a median of 5.5 and 3.4 per patient, respectively (ranges 2-6 and 0-6. respectively). WHO grade 3-4 toxicities for paclitaxel were: neutropenia in two patients (4/) and peripheral neuropathy in five (10%). Two patients had allergic reactions requiring paclitaxel withdrawal, whereas four (8%) had hyperglycemia >250 mg/ml. Grade 3-4 toxicities for CGV were: neutropenia in ten patients (20%), peripheral neuropathy in six (12%), anemia in four (8%), nausea/vomiting in five (10%). thrombocytopenia in two (4%), and fatigue in four (8%)., Conclusion: Our results suggest that sequential chemotherapy with weekly paclitaxel followed by CGV is highly active in patients with advanced NSCLC and has an acceptable toxicity. This schedule deserves further evaluation in a phase III study.

p53 oncoprotein expression was investigated in small cell lung carcinomas (SCLC) using immunohistochemical staining with antibodies against p53. A total of 50 pre-treatment biopsies were examined. We analyzed the relationship between p53 expression and these patients' relevant clinical characteristics, response to chemotherapy, time to progression, and overall survival. We found p53 overexpression in 46% of the samples but no association with clinical data or overall survival. Our results show a strong correlation of p53 staining with chemotherapy response. Multivariate analysis selected p53 as an independent predictive factor of chemotherapy response.

Background: Use of chemotherapy for advanced pancreatic carcinoma (APC) pursues a palliative objective. Gemcitabine is active against this tumor and shows in vitro synergism with 5-fluorouracil. UFT is a combination of tegafur (a prodrug of 5-flouorouracil) and uracil that can be given orally. The administration of UFT for several weeks may simulate the effects of a continuous infusion of 5-fluorouracil. The objective of the current study was to assess the efficacy and toxicity of the combination gemcitabine-UFT-leucovorin in the treatment of APC., Methods: Forty-two patients with bidimensionally measurable APC were included. The study regimen consisted of gemcitabine 1000 mg/m(2) once weekly for 3 consecutive weeks, followed by a 1-week rest, intravenous 6S-steroisomer of leucovorin (6SLV) 250 mg/m(2) in 2 hours on Day 1, oral 6SLV 7.5 mg/12 hours on Days 2-14, and oral UFT 390 mg/m(2)/day (in 2 doses) on Days 1-14. Cycles were repeated every 4 weeks for a minimum of 3 per patient unless progressive disease was detected., Results: One hundred eighty-three courses were given, with a median of 4 per patient. World Health Organization Grade 3-4 toxicity was: diarrhea in 7 patients (17%), leucopenia in 2 (5%), nausea/vomiting in 2 (5%), and anemia in 1 (4%). Among 38 patients evaluable for response, 6 achieved a partial response (16%; 95% confidence interval (CI), 6-31. 4), 15 had stable disease (39%), and 17 had progression (45%). Improvement in performance status and symptoms (pain, analgesic consumption, and weight) was present in 11 (29%) and 17 (45%) patients, respectively. Eighteen patients (47%; 95% CI, 31.5-54.5) experienced a clinical benefit response., Conclusions: The combination of gemcitabine-UFT-6SLV is convenient and moderately active and shows a low toxicity for the palliative treatment of patients with APC., (Copyright 2000 American Cancer Society.)

Gastric cancer is the most chemosensitive adenocarcinoma among digestive neoplasms. A few years ago, we performed a phase II trial with the FLEP regimen, in which fluorouracil (5-FU) and leucovorin are combined with etoposide and cisplatin (Platinol). This regimen resulted in a 39% response rate and high toxicity. Then we used the combination UFT (tegafur and uracil)/leucovorin/etoposide: UFT 390 mg/m2/day orally on days 1 to 14; leucovorin 500 mg/m2 i.v. day 1, and 15 mg/12 h orally on days 2 to 14; and etoposide 100 mg/m2 i.v. on day 1 and then 200 mg/m2/day orally on days 2 and 3. Forty-six patients received a median of five courses. Five patients (11%) achieved a complete response and 12 (26%) a partial response, for an overall response rate of 37%. The response rate was 50% in patients with an Eastern Cooperative Oncology Group performance status of 0 to 1. Grades 3 to 4 toxicities appeared as follow: 17% of patients had diarrhea, 11% had nausea/vomiting, and 13% of patients had anemia. One patient died of neutropenia and sepsis. The median survival time was 9 months. In summary, UFT/leucovorin/etoposide is effective and moderately toxic in patients with advanced gastric cancer. A new trial with UFT/leucovorin/epirubicin is ongoing.

Background: In spite of the high prevalence of cancer in the elderly, little information is available about the efficacy and toxicity of chemotherapy in elderly patients. In a previous study, the authors demonstrated that the combination of uracil and tegafur (UFT) with leucovorin (LV) was active and well tolerated in patients with advanced colorectal carcinoma (ACC). The objective of the current study was to determine the efficacy and toxicity of this regimen in elderly patients with ACC., Methods: Thirty-eight unselected patients older than 70 years (median age, 74 years) with measurable ACC were included. All patients were evaluable for toxicity and response. The regimen consisted of intravenous LV 500 mg/m2 on Day 1, oral LV 15 mg every 12 hours on Days 2-14, and oral UFT 390 mg/m2 on Days 1-14. Treatment was repeated every 28 days for a minimum of 4 courses per patient., Results: Two hundred eighty-eight cycles of chemotherapy were delivered (median, 7 per patient). Two patients (5%) achieved a complete response and 9 (24%) a partial response, for an overall response rate of 29%. Toxicity was mild, without dose-limiting myelosuppression. Four patients (10%) experienced Grade 3-4 diarrhea, 1 patient had Grade 3-4 nausea/vomiting, and 1 had Grade 3-4 mucositis. Grade 3-4 toxicity was more frequent among women than men (38% vs. 4%, P < 0.05)., Conclusions: Treatment with oral UFT modulated with LV is effective, well tolerated, and feasible on an outpatient basis for elderly patients with ACC. However, elderly women should be followed closely for the early detection of toxicity.

A phase II trial of UFT (Tegafur and Uracil) modulated by leucovorin was undertaken by the Oncopaz Cooperative Group to assess the efficacy and toxicity of this combination in patients with advanced colorectal cancer. A total of 75 patients were given 500 mg/m2 intravenous leucovorin and 195 mg/m2 of oral UFT on day 1, followed by oral leucovorin 15 mg/12 h and 195 mg/m2/12 h of oral UFT on days 2-14. An overall response rate of 39% was obtained, with seven complete responses (9%), and 22 partial responses (29%). The primary toxicity was gastrointestinal, with grade 1-2 diarrhea occurring in 8.5% of courses, and grade 3-4 in 3.5%. Hematologic toxicity was minimal, and there were no deaths due to toxicity. This regimen was active and well tolerated in patients with advanced colorectal cancer, including those 70 years of age or older.

Cisplatin (P) and 5-fluorouracil (5FU) have demonstrated activity for the treatment of squamous cell carcinoma of the esophagus. Previous studies have shown that leucovorin (L) may potentiate the antitumoral activity of 5FU, so we tested the combination P-5FU-L in 31 patients with inoperable squamous cell esophageal carcinoma. Chemotherapy consisted of P 20 mg/m2 in 4 h, followed by L 200 mg/m2 in 2 h and 5FU 600 mg/m2 in 18 h. This schedule was repeated for 5 days every 4 weeks. The treatment plan included three courses of chemotherapy followed by radiotherapy. The overall response rate was 58% (95% CI = 39-76%), with one complete remission (3%), and 61% of patients reported an improvement in dysphagia. Gastrointestinal toxicity was the main side effect: grade 3-4 mucositis appeared in 19% of patients, grade 3-4 nausea/vomiting in 13%, and grade 3-4 diarrhea in 6.5%. There was one toxic death caused by neutropenia and sepsis. Nineteen patients received local radiotherapy after chemotherapy, which increased the overall response rate to 63% (5% complete responses). Dysphagia improved in 75% of them. The median survival for all patients was 11 months. This study shows that sequential therapy with P-5FU-L and radiotherapy achieves a high response rate as well as adequate symptomatic relief in patients with inoperable esophageal cancer. The results justify further evaluation of P-5FU-L in patients with earlier-stage disease.

We performed a phase II study to assess the efficacy and toxicity of the cisplatin-UFT-leucovorin (LV) combination in patients with advanced non-small-cell lung cancer (NSCLC). Twenty-five patients with measurable disease who had not received prior chemotherapy were entered into the trial. The therapeutic regimen consisted of cisplatin 90 mg/m(2) and i.v. LV 500 mg/m(2) on day 1, followed by oral UFT 390 mg/m(2)/day (in two doses on days 1 through 14. Patients also received oral LV 15 mg/12 h on days 2 through 14. Seventeen patients required reduced doses of UFT (200 mg/m(2) due to toxicity. Courses were repeated every 28 days for a minimum of three per patient. Three of 25 patients (12%) achieved a partial response (95% CI: 2.6 to 32.2%), two with 390 mg/m(2)/day and one with 200 mg/m(2)/day of UFT. The main side effects were hematological and gastrointestinal. In the courses including 390 mg/m(2)/day of UFT, grade 3-4 toxicity was leucopenia in 18% of the courses, nausea/vomiting in 27%, and diarrhea and epigastralgia in 13% each. Grade 3-4 toxicities for 200 mg/m(2)/day of UFT were leucopenia 2%, nausea/vomiting 9% and diarrhea 7%. In conclusion, this regimen cannot be recommend for the treatment of advanced NSCLC due to its low response rate and high toxicity.